In the absence of an efficient vaccine, prevention of HIV transmission remains the primary and economically feasible infection prevention method available to date. Unfortunately, condoms have remained the single most effective method available to date, and such prevention method is not necessarily available or acceptable in certain communities. Thus the rationale for well tolerated and efficacious microbicides are a given as highlighted in this proposal. Unfortunately, previous clinical trials with promising microbicide formulations have not only failed to protect from transmission but in certain cases have even had the opposite effect by facilitating viral passage through the mucosa. These findings dictate the need for thorough pre-clinical safety and efficacy testing using an animal model representative of man. This project aims to use the nonhuman primate model to fulfill these pre-requisites before moving to the clinical arena. The project will therefore utilize a total of 55 cycling female cynomolgus macaques to evaluate the biodistribution, pharmacokinetics and potential localized and systemic toxicity of HEC gel versus vaginal rings or mucoadhesive films formulated to release monoclonal antibodies capable of neutralizing a wide variety of HIV isolates and HSV-2gD into the vaginal environment. An initial dose finding study will be performed to identify protective doses for each HIV Mab against multiple low dose esposures to a clade B SHIV. This data will be used to formulate a combined Mab dose to deliver via films or intravaginal rings as compared to gel. After completion of pharmacokinetics and pharmacodynamic studies, this combination delivered via stable mucoadhesive films will be tested for protective efficacy against repeated low dose SHIV challenges. Finally, in aim 4, we will compare delivery of the Mabs via IVR to films for protective efficacy against multiple vaginal exposures to either a clade B or C SHIV with a final high dose challenge as a final test of protection. Outcome of these preclinical studies will provide invaluable data for the validation and optimization of subsequent phase I and II human clinical trials.